Oliveira Laerte, Costa-Neto Claudio M, Nakaie Clovis R, Schreier Shirley, Shimuta Suma I, Paiva Antonio C M
Department of Biophysics, Escola Paulista de Medicina, Federal University of São Paulo, Brazil.
Physiol Rev. 2007 Apr;87(2):565-92. doi: 10.1152/physrev.00040.2005.
The most prevalent physiological effects of ANG II, the main product of the renin-angiotensin system, are mediated by the AT1 receptor, a rhodopsin-like AGPCR. Numerous studies of the cardiovascular effects of synthetic peptide analogs allowed a detailed mapping of ANG II's structural requirements for receptor binding and activation, which were complemented by site-directed mutagenesis studies on the AT1 receptor to investigate the role of its structure in ligand binding, signal transduction, phosphorylation, binding to arrestins, internalization, desensitization, tachyphylaxis, and other properties. The knowledge of the high-resolution structure of rhodopsin allowed homology modeling of the AT1 receptor. The models thus built and mutagenesis data indicate that physiological (agonist binding) or constitutive (mutated receptor) activation may involve different degrees of expansion of the receptor's central cavity. Residues in ANG II structure seem to control these conformational changes and to dictate the type of cytosolic event elicited during the activation. 1) Agonist aromatic residues (Phe8 and Tyr4) favor the coupling to G protein, and 2) absence of these residues can favor a mechanism leading directly to receptor internalization via phosphorylation by specific kinases of the receptor's COOH-terminal Ser and Thr residues, arrestin binding, and clathrin-dependent coated-pit vesicles. On the other hand, the NH2-terminal residues of the agonists ANG II and [Sar1]-ANG II were found to bind by two distinct modes to the AT1 receptor extracellular site flanked by the COOH-terminal segments of the EC-3 loop and the NH2-terminal domain. Since the [Sar1]-ligand is the most potent molecule to trigger tachyphylaxis in AT1 receptors, it was suggested that its corresponding binding mode might be associated with this special condition of receptors.
血管紧张素II（肾素-血管紧张素系统的主要产物）最普遍的生理效应是由AT1受体介导的，AT1受体是一种视紫红质样G蛋白偶联受体（AGPCR）。对合成肽类似物心血管效应的大量研究使得能够详细描绘血管紧张素II与受体结合及激活的结构要求，同时对AT1受体进行的定点诱变研究也补充了这一点，以研究其结构在配体结合、信号转导、磷酸化、与阻遏蛋白结合、内化、脱敏、快速耐受性及其他特性中的作用。视紫红质高分辨率结构的知识使得能够对AT1受体进行同源建模。由此构建的模型和诱变数据表明，生理（激动剂结合）或组成性（突变受体）激活可能涉及受体中心腔不同程度的扩张。血管紧张素II结构中的残基似乎控制这些构象变化，并决定激活过程中引发的胞质事件类型。1）激动剂芳香族残基（苯丙氨酸8和酪氨酸4）有利于与G蛋白偶联，2）这些残基的缺失可能有利于一种直接导致受体内化的机制，该机制通过受体COOH末端丝氨酸和苏氨酸残基的特定激酶磷酸化、阻遏蛋白结合以及网格蛋白依赖的有被小窝囊泡来实现。另一方面，发现激动剂血管紧张素II和[Sar1]-血管紧张素II的NH2末端残基以两种不同模式结合到由EC-3环的COOH末端片段和NH2末端结构域侧翼的AT1受体细胞外位点。由于[Sar1]-配体是在AT1受体中引发快速耐受性的最有效分子，因此有人提出其相应的结合模式可能与受体的这种特殊状态有关。
